UBE2K-FBXO11 complex activates Wnt signaling by stabilizing β-catenin through lysine 63-linked polyubiquitination
Abstract
Abstract Β-catenin is regulated by phosphorylation and lysine (K)48-linked ubiquitination, which target it for proteasomal degradation. While the degradation machinery of β-catenin, including the destruction complex, has been extensively studied, regulators that stabilize β-catenin remain largely unexplored. A Wnt pathway double death trap (DDT) reporter system was established, followed by a genome-wide CRISPR screen that identified UBE2K and FBXO11 as novel positive regulators of Wnt signaling. Mechanistically, FBXO11 interacts with UBE2K to catalyze K63-linked polyubiquitination of β-catenin at residues K292 and K345, thereby enhancing its protein stability. Additionally, targeting the UBE2K-FBXO11 regulatory axis demonstrates a potent inhibitory effect on the growth of cancer cells driven by CTNNB1 mutations. This study reveals the UBE2K-FBXO11 complex as a previously unrecognized E2-E3 ubiquitination module that positively regulates β-catenin stability, thereby expanding the understanding of ubiquitin-mediated regulation of β-catenin beyond its canonical role in proteasomal degradation.
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Authors: Kai Xia, Zhengjin He, Jingchuan Ma, Yun Pan, Mingxian Liu, Yankai Chu, Yueru Xie, Huiling Fang, Shuo Chen, Pinyu Huang, Man Yang, Aowei Huang, Yao Tan, Luoqiu Zhang, Renyuan Gao, Tianqi Wu, Chunqiu Chen, Lu Yin, Moubin Lin, Hai Jiang
Institutions: Chinese Academy of Sciences, University of Chinese Academy of Sciences, Tongji University, Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine, Yangpu Hospital of Tongji University, Shanghai Tenth People's Hospital, Center for Excellence in Molecular Cell Science